The acid-labile drugs essentially comprise of substituted benzimidazole gastric anti-secretary agents, such as omeprazole, lansoprazole, pantoprazole, rabeprazole and pharmaceutically acceptable salts thereof. These agents are known proton pump inhibitors with powerful inhibitory action against secretion of gastric acid. They are indicated for the treatment of various digestive ulcers, are well known in the art and are described in U.S. Pat. No. 4,255,431.
It has been found that these benzimidazole derivatives are easily destroyed in the acid medium and thus are difficult to formulate for oral administration. Upon oral administration, the pharmaceutical composition comes in contact with gastric fluid in the stomach, which is highly acidic, leading to breakdown and loss of activity of the benzimidazole derivative.
Pharmaceutical compositions comprising acid labile drugs are protected from acidic gastric juices by an enteric coating. However most of the enteric coating materials are either themselves acidic in nature or contain acidic materials, which may react with the benzimidazole derivative and cause degradation.
The stability problems associated with benzimidazole compounds are well recognized in the prior art, which teaches various approaches for preparing stable formulations containing benzimidazole compounds. One of the most common approaches utilized to stabilize benzimidazole compounds, is the use of an alkaline core, followed by a separating layer and finally an enteric layer. It is also stated in the art that the use of fillers and binders in the core reduces the stability problems associated with benzimidazole derivatives. Several prior art documents describe such compositions that are suitable for oral administration of acid-labile substances.
Lovgren et al., in U.S. Pat. No. 4,786,505, describe a stable pharmaceutical preparation of omeprazole that resist acid attack, but dissolves rapidly in neutral or alkaline media. Particles of omeprazole are mixed with water-soluble alkaline-reacting substances and the particles are coated with a “separating layer” that acts as a pH-buffering zone to prevent contact of the drug and acidic groups that are present in the final enteric coating material which forms the outermost coated layer.
U.S. Pat. No. 4,853,230 assigned to Aktiebolaget Hassle, discloses a pharmaceutical preparation containing an acid labile compound together with an alkaline reacting compound or an alkaline salt of an acid labile compound optionally together with an alkaline compound as the core material, one or more seal coating layers comprising inert reacting compounds which are soluble or rapidly disintegrating in water, or polymeric, water soluble film forming compounds, optionally containing pH-buffering alkaline compounds and then are coated with an enteric film-forming material.
U.S. Pat. No. 5,997,903 assigned to Byk Golden Lomberg Chem Fab, covers an orally administrable medicament in pellet or tablet form comprising a core in which active compound or its physiologically-tolerated salt is admixed with binder, filler, a basic inorganic compound and, optionally, a member selected from the group consisting of another tablet auxiliary and the core is coated with an inert water-soluble intermediate layer and an outer layer which is resistant to gastric juice. The patent claims pantoprazole as the active ingredient, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose as the binder and mannitol as filler. According to Dietrich et al., the use of mannitol as the sole filler for tablets requires a suitable binder, which imparts adequate hardness to the core. The equivalent European Patent, EP0589981 relates to oral medicament of acid labile compounds, which have a core containing pantoprazole as an active ingredient mixed with one or more binders, fillers, optionally one or more basic physiologically tolerated inorganic compounds and other tablet auxiliaries and the core is coated with a water soluble intermediate layer, then are coated with a gastric juice resistant outer layer.
U.S. Pat. No. 5,035,899 to Saeki et al., relates to compositions of acid-unstable drugs, which are protected against contact with gastric acid. A core that contains the drug is coated first with fine particles of a material having low water solubility, then coated with enteric film forming material.
Sachs et al., in U.S. Pat. No. 6,274,173 disclosed a controlled release pharmaceutical composition that includes an acid labile proton pump inhibitor other than pantoprazole, an alkaline pellet or tablet core, at least one water insoluble intermediate layer which controlled the release of the active ingredient, and an outer enteric layer which was soluble in the intestine. The seal coating was described as controlling the release of the active ingredient and thereby the active ingredient was released in a modified release manner, i.e., part of the active ingredient was released in immediate manner and part was released in controlled manner.
U.S. Pat. No. 6,602,522 assigned to Andrx Pharmaceuticals, discloses pharmaceutical composition of omeprazole for oral administration which includes a core component containing a therapeutically effective amount of an acid-labile compound, for example, substituted benzimidazole, such as, omeprazole, an optional surface active agent, a filler, a pharmaceutically acceptable alkaline agent, a binder; and a single layer of coating on said core which comprises a layer of an enteric coating agent.
A need exists for a drug-containing dosage form in which drug substances will not be exposed to acid in the stomach, but will be rapidly released when the dosage form enters a more alkaline environment and at the same time the composition must be stable.